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Clonality analysis of synchronous lesions of cervical carcinoma based on X chromosome inactivation polymorphism, human papillomavirus type 16 genome mutations, and loss of heterozygosity.

Hu X, Pang T, Asplund A, Pontén J, Nistér M - J. Exp. Med. (2002)

Bottom Line: Microdissection was performed on 24 samples from this case, representing the entire lesional situation.The combination of different X chromosome inactivation patterns, two HPV16 point mutations, and LOH at three genomic microsatellite loci, led to the identification of five different "monoclonal" lesions (CIN II, CIN III, and invasive carcinoma nests) and five different "polyclonal" areas (CIN II and normal squamous epithelium).Our results also supported the view that HPV16 as a "field factor" causes cervical carcinoma, which is probably promoted by the loss of chromosomal material as indicated by the LOH.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden. hu.xinrong@genpat.uu.se

ABSTRACT
One of the most common forms of carcinoma in women, cervical invasive squamous cell carcinoma (CIC), often coexists with multiple lesions of cervical intraepithelial neoplasia (CIN). CIC and CIN show heterogeneity with respect to both histopathology and biology. To understand the causes, origin, and model of progression of cervical carcinoma, we assessed the clonality of a case with multiple synchronous lesions by analyzing X chromosome inactivation polymorphism, human papillomavirus type 16 (HPV16) sequence variation/mutations, and loss of heterozygosity (LOH). Microdissection was performed on 24 samples from this case, representing the entire lesional situation. The combination of different X chromosome inactivation patterns, two HPV16 point mutations, and LOH at three genomic microsatellite loci, led to the identification of five different "monoclonal" lesions (CIN II, CIN III, and invasive carcinoma nests) and five different "polyclonal" areas (CIN II and normal squamous epithelium). This finding indicated that CIC can originate from multiple precursor cells, from which some clones might progress via multiple steps, namely via CIN II and CIN III, whereas others might develop independently and possibly directly from the carcinoma precursor cells. Our results also supported the view that HPV16 as a "field factor" causes cervical carcinoma, which is probably promoted by the loss of chromosomal material as indicated by the LOH.

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Electropherograms showing LOH analyzed at three different microsatellite loci. (1), (5), and (8) are normal tissue (H2-2), and the others are CIN or invasive carcinoma samples. (1)–(4), D6S311 (231 bp, 237 bp); (2), long allele remains (H2-3); (3), short allele remains (H2-7); (4), both alleles remain (H2-8); (5)–(7), D3S659 (101 bp, 105 bp); (6), short allele remains (H2-3); (7), both alleles remain (H2-8); (8)–(10), D3S1283 (149 bp, 156 bp); (9), long allele remains (H2-3); (10), both alleles remain (H2-8).
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fig5: Electropherograms showing LOH analyzed at three different microsatellite loci. (1), (5), and (8) are normal tissue (H2-2), and the others are CIN or invasive carcinoma samples. (1)–(4), D6S311 (231 bp, 237 bp); (2), long allele remains (H2-3); (3), short allele remains (H2-7); (4), both alleles remain (H2-8); (5)–(7), D3S659 (101 bp, 105 bp); (6), short allele remains (H2-3); (7), both alleles remain (H2-8); (8)–(10), D3S1283 (149 bp, 156 bp); (9), long allele remains (H2-3); (10), both alleles remain (H2-8).

Mentions: Analysis was successful and informative for D3S659 (101 bp, 105 bp), D3S1283 (150 bp, 156 bp), and D6S311 (231 bp, 237 bp) in all samples (Fig. 5) . Loss of the long allele for D3S659 and of the short allele for D3S1283 occurred. Most samples with LOH at D6S311 had lost the short allele, whereas one had lost the long allele. None of the normal samples, squamous epithelium, gland and stroma, nor the superficially invasive carcinoma sample (H2-8), showed loss at any of these three microsatellite markers. The detailed information showing that LOH occurred in most lesion samples is given in Table II.


Clonality analysis of synchronous lesions of cervical carcinoma based on X chromosome inactivation polymorphism, human papillomavirus type 16 genome mutations, and loss of heterozygosity.

Hu X, Pang T, Asplund A, Pontén J, Nistér M - J. Exp. Med. (2002)

Electropherograms showing LOH analyzed at three different microsatellite loci. (1), (5), and (8) are normal tissue (H2-2), and the others are CIN or invasive carcinoma samples. (1)–(4), D6S311 (231 bp, 237 bp); (2), long allele remains (H2-3); (3), short allele remains (H2-7); (4), both alleles remain (H2-8); (5)–(7), D3S659 (101 bp, 105 bp); (6), short allele remains (H2-3); (7), both alleles remain (H2-8); (8)–(10), D3S1283 (149 bp, 156 bp); (9), long allele remains (H2-3); (10), both alleles remain (H2-8).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193730&req=5

fig5: Electropherograms showing LOH analyzed at three different microsatellite loci. (1), (5), and (8) are normal tissue (H2-2), and the others are CIN or invasive carcinoma samples. (1)–(4), D6S311 (231 bp, 237 bp); (2), long allele remains (H2-3); (3), short allele remains (H2-7); (4), both alleles remain (H2-8); (5)–(7), D3S659 (101 bp, 105 bp); (6), short allele remains (H2-3); (7), both alleles remain (H2-8); (8)–(10), D3S1283 (149 bp, 156 bp); (9), long allele remains (H2-3); (10), both alleles remain (H2-8).
Mentions: Analysis was successful and informative for D3S659 (101 bp, 105 bp), D3S1283 (150 bp, 156 bp), and D6S311 (231 bp, 237 bp) in all samples (Fig. 5) . Loss of the long allele for D3S659 and of the short allele for D3S1283 occurred. Most samples with LOH at D6S311 had lost the short allele, whereas one had lost the long allele. None of the normal samples, squamous epithelium, gland and stroma, nor the superficially invasive carcinoma sample (H2-8), showed loss at any of these three microsatellite markers. The detailed information showing that LOH occurred in most lesion samples is given in Table II.

Bottom Line: Microdissection was performed on 24 samples from this case, representing the entire lesional situation.The combination of different X chromosome inactivation patterns, two HPV16 point mutations, and LOH at three genomic microsatellite loci, led to the identification of five different "monoclonal" lesions (CIN II, CIN III, and invasive carcinoma nests) and five different "polyclonal" areas (CIN II and normal squamous epithelium).Our results also supported the view that HPV16 as a "field factor" causes cervical carcinoma, which is probably promoted by the loss of chromosomal material as indicated by the LOH.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden. hu.xinrong@genpat.uu.se

ABSTRACT
One of the most common forms of carcinoma in women, cervical invasive squamous cell carcinoma (CIC), often coexists with multiple lesions of cervical intraepithelial neoplasia (CIN). CIC and CIN show heterogeneity with respect to both histopathology and biology. To understand the causes, origin, and model of progression of cervical carcinoma, we assessed the clonality of a case with multiple synchronous lesions by analyzing X chromosome inactivation polymorphism, human papillomavirus type 16 (HPV16) sequence variation/mutations, and loss of heterozygosity (LOH). Microdissection was performed on 24 samples from this case, representing the entire lesional situation. The combination of different X chromosome inactivation patterns, two HPV16 point mutations, and LOH at three genomic microsatellite loci, led to the identification of five different "monoclonal" lesions (CIN II, CIN III, and invasive carcinoma nests) and five different "polyclonal" areas (CIN II and normal squamous epithelium). This finding indicated that CIC can originate from multiple precursor cells, from which some clones might progress via multiple steps, namely via CIN II and CIN III, whereas others might develop independently and possibly directly from the carcinoma precursor cells. Our results also supported the view that HPV16 as a "field factor" causes cervical carcinoma, which is probably promoted by the loss of chromosomal material as indicated by the LOH.

Show MeSH
Related in: MedlinePlus